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A two-amino-acid substitution in the transcription factor ROR?t disrupts its function in TH17 differentiation but not in thymocyte development.

ABSTRACT: The transcription factor ROR?t regulates differentiation of the TH17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of ROR?t prevents TH17 cell-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in ROR?t (ROR?tM) that 'preferentially' disrupted TH17 differentiation but not thymocyte development. Mice expressing ROR?tM were resistant to EAE associated with defective TH17 differentiation but maintained normal thymocyte development and normal lymph-node genesis, except for Peyer's patches. ROR?tM showed less ubiquitination at Lys69 that was selectively required for TH17 differentiation but not T cell development. This study will inform the development of treatments that selectively target TH17 cell-mediated autoimmunity but do not affect thymocyte development or induce lymphoma.

SUBMITTER: He Z 

PROVIDER: S-EPMC5678981 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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A two-amino-acid substitution in the transcription factor RORγt disrupts its function in T<sub>H</sub>17 differentiation but not in thymocyte development.

He Zhiheng Z   Ma Jian J   Wang Ruiqing R   Zhang Jing J   Huang Zhaofeng Z   Wang Fei F   Sen Subha S   Rothenberg Ellen V EV   Sun Zuoming Z  

Nature immunology 20170828 10

The transcription factor RORγt regulates differentiation of the T<sub>H</sub>17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of RORγt prevents T<sub>H</sub>17 cell-mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in RORγt (RORγt<sup>M</sup>) that 'preferentially' disrupted T<sub>H</sub>17 differentiation  ...[more]

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